In vitro antiplasmodial activity-directed investigation and UPLC–MS fingerprint of promising extracts and fractions from Terminalia ivorensis A. Chev. and Terminalia brownii Fresen.

Please read abstract in the article.The Grand Challenges Africa programme is supported by the African Academy of Sciences (AAS), Bill & Melinda Gates Foundation (BMGF), Medicines for Malaria Venture (MMV), and Drug Discovery and Development Centre of University of Cape Town (H3D).https://www.elsevier.com/locate/jethpharm2023-07-09hj2023Chemistr

Chemical constituents of two Cameroonian medicinal plants: Sida rhombifolia L. and Sida acuta Burm. f. (Malvaceae) and their antiplasmodial activity

Kamdoum BC, Simo I, Wouamba SCN, et al. Chemical constituents of two Cameroonian medicinal plants: Sida rhombifolia L. and Sida acuta Burm. f. (Malvaceae) and their antiplasmodial activity. Natural product research. 2021.An extensive phytochemical investigation of the EtOH/H2O (7:3) extracts of Sida rhombifolia L. and Sida acuta Burm. f., yielded a previously undescribed ceramide named rhombifoliamide (1) and a xylitol dimer (2), naturally isolated here for the first time, as well as the thirteen known compounds viz, oleanolic acid (3), beta-amyrin glucoside (4), ursolic acid (5), beta-sitosterol glucoside (6), tiliroside (7), 1,6-dihydroxyxanthone (8), a mixture of stigmasterol (9) and beta-sitosterol (10), cryptolepine (11), 20-Hydroxyecdysone (12), (E)-suberenol (13), thamnosmonin (14) and xanthyletin (15). Their structures were elucidated by the analyses of their spectroscopic and spectrometric data (1D and 2D NMR, and HRESI-MS) and by comparison with the previously reported data. The crude extracts, fractions, and some isolated compounds were tested against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains. All the tested samples demonstrated moderate and/or significant activities against 3D7 (IC50 values: 0.18-20.11g/mL) and Dd2 (IC50 values: 0.74-63.09g/mL)

In Vivo Antiplasmodial Activity of Terminalia mantaly Stem Bark Aqueous Extract in Mice Infected by Plasmodium berghei

Background. Terminalia mantaly is used in Cameroon traditional medicine to treat malaria and related symptoms. However, its antiplasmodial efficacy is still to be established. Objectives. The present study is aimed at evaluating the in vitro and in vivo antiplasmodial activity and the oral acute toxicity of the Terminalia mantaly extracts. Materials and Methods. Extracts were prepared from leaves and stem bark of T. mantaly, by maceration in distilled water, methanol, ethanol, dichloromethane (DCM), and hexane. All extracts were initially screened in vitro against the chloroquine-resistant strain W2 of P. falciparum to confirm its in vitro activity, and the most potent one was assessed in malaria mouse model at three concentrations (100, 200, and 400 mg/kg/bw). Biochemical, hematological, and histological parameters were also determined. Results. Overall, 7 extracts showed in vitro antiplasmodial activity with IC50 ranging from 0.809 μg/mL to 5.886 μg/mL. The aqueous extract from the stem bark of T. mantaly (Tmsbw) was the most potent (IC50=0.809 μg/mL) and was further assessed for acute toxicity and efficacy in Plasmodium berghei-infected mice. Tmsbw was safe in mice with a median lethal dose (LD50) higher than 2000 mg/kg of body weight. It also exerted a good antimalarial efficacy in vivo with ED50 of 69.50 mg/kg and had no significant effect on biochemical, hematological, and histological parameters. Conclusion. The results suggest that the stem bark extract of T. mantaly possesses antimalarial activity

In vitro antiplasmodial activity and toxicological profile of extracts, fractions and chemical constituents of leaves and stem bark from Dacryodes edulis (Burseraceae)

Dongmo KJJ, Tali MBT, Fongang YSF, et al. In vitro antiplasmodial activity and toxicological profile of extracts, fractions and chemical constituents of leaves and stem bark from Dacryodes edulis (Burseraceae). BMC Complementary Medicine and Therapies. 2023;23(1): 211.BACKGROUND: Dacryodes edulis is a plant that belongs to the Burseraceae family. It is widely used traditionally alone or in association with other plants in Cameroonian folk medicine to cure wounds, fever, headaches, and malaria. The aim of this work was to investigate the leaves and stem bark of D. edulis with an emphasis on the antiplasmodial and cytotoxic effects of extracts, fractions, and isolated compounds.; METHODS: Extracts, fractions, and some isolated compounds were subjected to antiplasmodial activity screening in vitro against chloroquine-sensitive 3D7 and multidrug resistant Dd2 strains of Plasmodium falciparum using a SyBr Green fluorescence-based assay. The cytotoxicity of active extracts, fractions, and compounds was tested against mammalian Raw cell lines using an in vitro resazurin-based viability assay. The structures of the compounds were determined based on their NMR and MS data. The in vivo toxicity using female BALB/c mice was performed on the most active extract according to the protocol of OECD (2002), guideline 423.; RESULTS: The hydroethanolic extract from the leaves of D. edulis displayed good antiplasmodial activity with IC50 values of 3.10 and 3.56mug/mL respectively on sensitive (3D7) and multiresistant (Dd2) strains of P. falciparum. Of the sixteen compounds isolated, 3,3',4-tri-O-methylellagic acid (4) exhibited the highest antiplasmodial activity against PfDd2 strains with an IC50 value of 0.63mug/mL. All extracts, fractions, and isolated compounds demonstrated nocytotoxicity against Raw cell lines with CC50>250mug/mL. In addition, the most active extract on both strains of P. falciparum was nontoxic in vivo, with a LD50 greater than 2000 and 5000mg/kg. A phytochemical investigation of the stem bark and leaves of D. edulis afforded sixteen compounds, including two xanthones (1-2), three ellagic acid derivatives (3-5), one phenolic compound (6), one depside (7), one triglyceride (8), one auranthiamide acetate (9), one gallic acid derivative (10), four triterpenoids (11-14), and two steroids (15-16). Compounds 1, 2, 5, 7, 8, and 9 were herein reported for the first time from the Burseraceae family.; CONCLUSION: This work highlights the good in vitro antiplasmodial potency of the hydroethanolic extract of the leaves of this plant and that of two isolated constituents (3,3',4-tri-O-methylellagic acid and ethylgallate) from the plant. These biological results support the use of D. edulis in traditional medicine against malaria. © 2023. The Author(s)

Preliminary Structure–Activity Relationship Study of the MMV Pathogen Box Compound MMV675968 (2,4-Diaminoquinazoline) Unveils Novel Inhibitors of Trypanosoma brucei brucei

New drugs are urgently needed for the treatment of human African trypanosomiasis (HAT). In line with our quest for novel inhibitors of trypanosomes, a small library of analogs of the antitrypanosomal hit (MMV675968) available at MMV as solid materials was screened for antitrypanosomal activity. In silico exploration of two potent antitrypanosomal structural analogs (7-MMV1578647 and 10-MMV1578445) as inhibitors of dihydrofolate reductase (DHFR) was achieved, together with elucidation of other antitrypanosomal modes of action. In addition, they were assessed in vitro for tentative inhibition of DHFR in a crude trypanosome extract. Their ADMET properties were also predicted using dedicated software. Overall, the two diaminoquinazoline analogs displayed approximately 40-fold and 60-fold more potency and selectivity in vitro than the parent hit, respectively (MMV1578445 (10): IC50 = 0.045 µM, SI = 1737; MMV1578467 (7): IC50 = 0.06 µM; SI = 412). Analogs 7 and 10 were also strong binders of the DHFR enzyme in silico, in all their accessible protonation states, and interacted with key DHFR ligand recognition residues Val32, Asp54, and Ile160. They also exhibited significant activity against trypanosome protein isolate. MMV1578445 (10) portrayed fast and irreversible trypanosome growth arrest between 4–72 h at IC99. Analogs 7 and 10 induced in vitro ferric iron reduction and DNA fragmentation or apoptosis induction, respectively. The two potent analogs endowed with predicted suitable physicochemical and ADMET properties are good candidates for further deciphering their potential as starting points for new drug development for HAT

New lignan glycosides from Justicia secunda Vahl (Acanthaceae) with antimicrobial and antiparasitic properties

Three new lignan glucosides, namely, justisecundosides A (1), B (2a), and C (2b), were isolated from the whole plant of Justicia secunda together with seven known compounds (3−9). Their structures were established based on a comprehensive analysis of HR-ESI-MS, IR, UV, and CD, in conjunction with their 1D and 2D-NMR data. A putative biogenetic pathway of compounds 1−2a,b from coniferyl alcohol was proposed. In addition, the antimicrobialactivities of the extract, fractions, and some isolated compounds were assessed against multiresistant bacterial and fungal strains. Furthermore, the antiplasmodial, antileishmanial, and antitrypanosomal activities were assessed against the sensitive (3D7) and multidrug-resistant (Dd2) strains of P. falciparum, promastigote and bloodstream forms of L. donovani, and Trypanosoma brucei, respectively. Compound 4 exhibited moderate antibacterial activity against Staphylococcus aureus SA RN 46003 with a MIC value of 62.5 μg/mL. Besides, compound 6 demonstrated a very good activity against sensitive (IC50 Pf3D7: 0.81 μg/mL) and multidrug-resistant (IC50 PfDd2: 14.61 μg/mL) strains of P. falciparum while compound 4 displayed good antitrypanosomal activity (IC50: 1.19 μg/mL). Also, compound 1 was the most active on the promastigote form of L. donovani with an IC50 of 13.02 μg/mL

Bio-guided isolation of anti-leishmanial natural products from Diospyros gracilescens L. (Ebenaceae)

Njanpa CAN, Wouamba SCN, Yamthe LRT, et al. Bio-guided isolation of anti-leishmanial natural products from Diospyros gracilescens L. (Ebenaceae). BMC Complementary Medicine and Therapies. 2021;21(1): 106.Background Plants represent an intricate and innovative source for the discovery of novel therapeutic remedies for the management of infectious diseases. The current study aimed at discovering new inhibitors of Leishmania spp., using anti-leishmanial activity-guided investigation approach of extracts from Diospyros gracilescens Gurke (1911) (Ebenaceae), targeting the extracellular (promastigotes) and intracellular (amastigotes) forms of Leishmania donovani. Methods The plant extracts were prepared by maceration using H(2)0: EtOH (30:70, v/v) and further fractionated using a bio-guided approach. Different concentrations of D. gracilescens extracts, fractions and isolated compounds were tested in triplicate against L. donovani promastigotes and amastigotes in vitro. The antileishmanial potency and cytotoxicity on RAW 264.7 cells were determined using the resazurin colorimetric assay. The time kill kinetic profile of the most active sample was also investigated. The structures of all compounds were elucidated on the basis of extensive spectroscopic analyses, including 1D and 2D NMR, and HR-ESI-MS and by comparison of their data with those reported in the literature. Results The hydroethanolic crude extract of D. gracilescens trunk showed the most potent antileishmanial activity (IC50 = 5.84 mu g/mL). Further fractionation of this extract led to four (4) fractions of which, the hexane fraction showed the most potent activity (IC50 = 0.79 mu g/mL), and seven (07) compounds that exhibited moderate potency (IC50 = 13.69-241.71 mu M) against L. donovani. Compound 1-deoxyinositol (7) inhibited the promastigote and amastigote forms of L. donovani with IC50 values of 241.71 mu M and 120 mu M respectively and also showed the highest selectivity against L. donovani promastigotes (SI > 5.04). To the best of our knowledge, the antileishmanial activity of this compound is being reported here for the first time. The promising hexane fraction showed significant inhibition of parasites growth at different concentrations, but with no evidence of cidal effect over an exposure period of 120 h. Conclusions The results obtained indicated that the hydroethanolic extract from the D. gracilescens trunk and the derived hexane fraction have very potent inhibitory effect on cultivated promastigotes and amastigotes of L. donovani parasite. The isolated compounds showed a lesser extent of potency and selectivity. However, further structure-activity-relationship studies of 1-deoxyinositol could lead to more potent and selective hit derivatives of interest for detailed drug discovery program against visceral leishmaniasis

Constituents from ripe figs of Ficus vallis-choudae Delile (Moraceae) with antiplasmodial activity

Chouna HSD, Dize D, Kagho DUK, et al. Constituents from ripe figs of Ficus vallis-choudae Delile (Moraceae) with antiplasmodial activity. Parasitology Research. 2022.Ripe figs, barks, and wood of Ficus vallis-choudae are used in traditional medicine against several conditions including nausea and malaria. However, its use is still to be scientifically documented and validated. Hence, the aim of the present work was to evaluate the antiplasmodial activity of the dichloromethane-methanol (DCM-MeOH (1:1)) crude extract, their hexane, dichloromethane, ethyl acetate, and methanoli fractions, as well as the isolated chemical constituents. The chemical study of the DCM-MeOH (1:1) crude extract of F. vallis-choudae figs led to the isolation of fifteen (15) known compounds identified based on their spectroscopic data [one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR), mass spectrometry] and by comparison of these data with those reported in the literature. Some of the isolated compounds were assessed in vitro for their antiplasmodial activity against Plasmodium falciparum chloroquine-sensitive 3D7 (Pf3D7) and multidrug-resistant Dd2 strains. The dichloromethane fraction exhibited very good antiplasmodial activity against both strains with IC50 values of 13.86mug/mL and 8.18mug/mL, respectively. Among the tested compounds, wighteone (2) was the most active against P. falciparum 3D7 (IC50=24.6±1.5muM) and Dd2 (IC50=11.9±2.4muM) strains. The obtained results could justify the traditional uses of F. vallis-choudae against malaria. Wighteone appears to be the most active ingredient. However, further consideration of this compound as starting point for antimalarial drug discovery will depend upon its selectivity of action towards Plasmodium parasites. HIGHLIGHTS: 15 (fifteen) compounds were isolated from the dichloromethane-methanol extract of Ficus vallis-choudae. Their structures were determined on the basis of their spectroscopic data. The dichloromethane fraction showed promising activities on the Pf3D7 and PfDd2 strains with IC50 values of 13.86 and 8.18g/mL, respectively. Wighteone was the most active compound against PfDd2 (IC50=11.9±2.4muM). © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature